Macrophage-derived foam cell formation is a milestone of the atherosclerotic lesion initiation and progression. The formation of foam cells results from the disruption of a homeostatic mechanism that manipulates the uptake, intracellular metabolism and efflux of cholesterol within macrophages. Although studies have yielded much information about the homeostatic mechanism, the molecular basis of foam cell formation remains to be fully understood. We hypothesize that RNase L is involved in the lipid homeostatic mechanism and disruption of such homeostasis by lack of RNase L leads to foam cell formation and impacts the development of atherosclerosis. The hypothesis is based on our published data and recent observations that deficiency of RNase L attenuated macrophage functions and mediated the expression of certain pro- and anti-foam cell genes in macrophages. In addition, lack of RNase L significantly increased the formation of foam cells from bone marrow derived macrophages (BMDMs) in our preliminary study. The increase of foam cell formation was associated with up- regulation of the expression of scavenger receptors such as CD36, SR-A, and PPAR-?. Furthermore, RNase L impacted the endoplasmic reticulum (ER)-associated degradation (ERAD)/proteasome pathway responsible for the feedback inhibition of cholesterol synthesis. The overall goal of this project is to systematically elucidate the role of RNase L in foam cell formation and lesion development in the animal model. Two specific aims are proposed: 1) Demonstrate that RNase L facilitates the uptake, intracellular metabolism, and/or efflux of cholesterol in macrophages and 2) Investigate the role of RNase L in the metabolic syndrome. These studies should mechanistic insights into foam cell formation and the development of atherosclerosis, novel therapeutic strategies for this disorder may be designed through the regulation of RNase L.